| Wellcome

Therapeutics

Controllable CAR-T cell therapy for relapsed refractory B cell leukaemia

Chimeric antigen receptor T (CAR-T) cell therapy is a form of gene or cell therapy for the treatment of cancer that has produced complete remissions in patients with acute lymphoblastic leukemia who have not responded to previous treatments. This has offered patients a realistic hope for a cure. However, challenges related to the inability to control the activity of a genetically engineered CAR-T cell once given to a patient has limited the use of this therapy.

Dr Travis Young and colleagues at the California Institute for Biomedical Research (Calibr) have developed a controllable CAR-T cell that provides safe and efficacious therapy. This has the potential to provide a potentially curative therapy while maintaining an acceptable safety margin for the treatment of patients.

They will produce material to support the use of engineered, recombinant antibody-based switches to control activity of sCAR-T cells in a first-in-human clinical trial for patients with relapse/refractory B cell leukemia.

Novel class of Gram-negative antibiotics to treat hospital-acquired infections from ESKAPE pathogens

Polyphor is working to advance the development of a broad-spectrum, Gram-negative antibiotic. The candidates are derived from the company’s macrocycle technology platform and have shown encouraging activity against the most resistant strains of Gram-negative pathogens.

This award will support improving the potency and spectrum of these compounds, and testing their in vivo efficacy in animal infection models.

Optimisation of small molecule inhibitors of SPRK1 for topical application in the treatment of wet age-related macular degeneration

Exudative age-related macular degeneration (wAMD) and diabetic macular oedema (DME) are the leading causes of blindness in the Western world. wAMD affects 1.3% of people over 50 years old, with a global incidence of 1.5 million. Diabetes affects 382 million people worldwide and this is expected to increase to 592 million by 2035.

Current treatment options for these conditions are limited. Anti-Vascular Endothelial Growth Factor (VEGF) agents improve vision in some patients and slow deterioration in most. However they must be administered by regular intravitreal injections, and they non-specifically block both pro-angiogenic and anti-angiogenic isoforms of VEGF. So there is an incentive to develop a non-invasive therapeutic modality with effective and safe agents.

Exonate has developed small molecules that inhibit production of pro-angiogenic VEGF through selective inhibition of serine/threonine-protein kinase 1 (SRPK1)-mediated VEGF splicing. These inhibitors have already demonstrated superior efficacy as topical agents in preclinical models of wAMD.

Through this project, Exonate will take several of these inhibitors into an optimisation programme, culminating in the nomination of a preclinical candidate drug with optimal characteristics for clinical development. The project will also involve assessing the candidate in regulatory toxicology and safety pharmacology studies to support an application to the regulatory authorities for clinical evaluation. The company expects to reach this milestone and enter the clinic in early 2020.

Alpha-GABa receptor modulators for the treatment of cognitive impairment associated with Huntington’s disease

Huntington's disease is a fatal genetic disease characterised by a movement disorder that is accompanied by a decline in cognitive function and changes in mood and behaviour. The decline in cognitive function may precede the movement disorder by a decade or more and is a very important component of the functional disability associated with the disease. There is, however, no effective treatment for enhancing cognitive performance in Huntington's. Professor John Atack at the University of Sussex aims to identify novel drugs that can enhance cognitive performance in subjects with Huntington's disease to address a large unmet medical need.

Developing drugs to treat myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It is a highly debilitating condition with an average life expectancy of 58 years, affecting more than 100,000 patients in developed countries. DM1 is primarily a neuromuscular disorder, which also affects a range of other systems including the heart, brain, endocrine and digestive systems. Patients may also show psychological dysfunction, cognitive impairment and excessive daytime sleepiness. There is no treatment for DM1 and all features show an obvious deterioration with time.

DM1 is caused by a repeat expansion mutation in the 3 untranslated region of the DMPK gene. Unaffected people have 5 to 30 copies of a CTG sequence whereas patients may have hundreds or sometimes thousands of copies. When expressed the DMPK expansion transcripts remain in the nucleus where they form distinct spots or foci.

Professors Chris Hayes and David Brook at the University of Nottingham developed an assay to screen for compounds that might provide a treatment for DM1. They identified small molecules that target a novel protein and destroy the spots in DM1 cells, thereby leading to a significant reduction in the faulty RNA and other molecular features of the disorder. This Seeding Drug Discovery award, in collaboration with Argenta Discovery, is based on targeting this novel protein, by generating unique molecules that are selective and more suitable for oral administration to patients. Professors Hayes and Brook anticipate that a successful drug would target most/all features of the disease.

Development of novel antagonists of the cell surface adrenomedullin 2 receptor for the treatment of pancreatic cancer

Pancreatic cancer is the 10th most common cancer, but in the next 15 years, it will become the second highest cause of cancer-related death. Unlike almost all other cancers, the prognosis has not changed in the last 30 years. After diagnosis, outcomes are very poor, with 1-year and 5-year survival rates of <25% and <5% respectively.

The best current therapies offer only a few months of increased life expectancy, and patients’ quality of life is poor despite palliative treatments. There is clearly a pressing need for better treatments for pancreatic cancer. A team from the University of Sheffield led by Professor Tim Skerry, with Peakdale Molecular and Sandexis Medicinal Chemistry have been awarded Seeding Drug Discovery funding to develop selective antagonists of the adrenomedullin-2 receptor.

Adrenomedullin is a hormone involved in cancer growth and spread, which also has important roles in the control of blood pressure. Adrenomedullin acts through two different receptors one of which mostly regulates blood pressure. The other has important roles in cancer biology. The team have shown that in model systems, blockade of the receptor reduces tumour growth and spread. They will develop their existing novel lead compounds to block the adrenomedullin-2 receptor and inhibit its important roles in cancer, while keeping its normal functions.

Development of hypoxia-activated DNA-PK inhibitors to enhance radiotherapy and improve outcomes for head and neck cancer

Radiotherapy is used to treat 50% of all cancers and about half of these are cured. In head and neck cancers, typical treatment includes radiation that is targeted to the tumour in combination with high dose cisplatin that can have serious side effects. Radiotherapy results in the greatest response with cisplatin improving treatment success by ~10%.

It has been known for decades that one of the main reasons radiotherapy fails is due to the presence of radiation-resistant cells that have little oxygen (termed hypoxia) and many studies in patients have confirmed that hypoxia in tumours is correlated with poor treatment outcomes.

Dr Andrew Minchinton and colleagues, from the BC Cancer Agency in Canada, propose to develop a drug that prevents hypoxic cells from repairing radiation-induced damage to their DNA. The drug is only active in regions with no oxygen and only impacts those cells within the radiation beam; therefore, the drug is highly selective for its activity in hypoxic tumours and may reduce the need for additional chemotherapies that impact patient quality of life. The net effect is that radiotherapy will have a stronger effect on the whole tumour as even the radiation-resistant hypoxic cells.

Development of small molecule directly acting non-entry inhibitors against the human respiratory syncytial virus

The aim of this project is to discover and develop potent and safe inhibitors of Respiratory Syncytial Virus (RSV) replication. Respiratory syncytial virus (RSV) is a virus that belongs, together with the measles, mumps and metapneumovirus to the family of Paramyxoviridae. This pathogen causes significant morbidity (bronchiolitis) and mortality in premature babies, in children under the age of one, in children with congenital heart and lung problems, in transplant patients and in immuno-compromised or elderly people.

Infection often requires prolonged hospitalisation, resulting in a high number of hospitalisation days during each epidemic season. Immunity against this virus is not long-lived and may allow re-infection every epidemic period. A vaccine is not available and prophylactic administration of humanised monoclonal antibodies is advised in high risk young infants. Access to potent RSV inhibitors for treating such infections is therefore highly needed. The teams of Prof. Johan Neyts of the Rega Institute, KU Leuven and of the Centre for Drug Design and Discovery (CD3) established by KU Leuven will collaborate to discover such new RSV inhibitors.

Development of novel, boron-containing small molecules for the treatment of Chagas

There is significant need for new treatments for Chagas disease. The disease is caused by the parasite Trypanosoma cruzi, and the disease can be spread by insect vectors, blood transfusions and from infected mothers to their newborn children.

Between 10 and 20 million people, mostly in Central and South America are infected with the parasite and the disease results in over 10,000 annual deaths. Chagas disease kills more people in Latin America than any other parasitic disease, including malaria. Increasing numbers of cases are also being documented outside the normal high transmission areas, including in the U.S. and Europe.

Although in use for more than four decades, the two drugs available to treat Chagas--benznidazole and nifurtimox-- require a long course of therapy (60-90 days), have serious safety concerns (20-30% side effects result in treatment discontinuation), fail to cure in a significant number of patients (a result of natural resistance of some isolates to current drugs), and are contraindicated in pregnancy.

Thus, there is a critical need for new drugs that address these significant shortcomings of existing therapeutics. Oxaboroles—pioneered by Anacor Pharmaceuticals--have emerged in preliminary studies as a class that can potentially fill this important need. The Wellcome Trust is funding a dedicated drug discovery effort at Anacor, partnered with the disease expertise in the laboratory of Professor Rick Tarleton of the University of Georgia. The objective of the project is to deliver a new drug candidate ready to enter clinical trials by 2016.

Inhibitors of protein arginine methyl transferase 5 (PRMT5) for the treatment of β-thalassemia and sickle cell disease

Haemoglobin is the major protein in red blood cells essential for transport of oxygen from the lungs to tissues. The disorders of haemoglobin production are the commonest genetic diseases world-wide, affecting a staggering 10% of the global population.

Two of these disorders, sickle cell disease (SCD) and β-thalassemia have devastating consequences for affected children, particularly in under-developed nations where effective therapies are unavailable. In SCD, children experience numerous episodes of extreme pain due to damage of many organs and die before their teens. Death from untreated β-thalassemia occurs within the first three years of life. Even with optimal treatment, both these disorders are associated with a greater than thirty year reduction in life expectancy and significantly impaired quality of life.

The ill effects of these diseases are dramatically reduced in a minute percentage of adult patients who have naturally raised levels of the form of haemoglobin produced by the developing baby, fetal haemoglobin. Dr Ian Smith and colleagues at Cancer Therapeutics CRC Pty Ltd have identified a means to elevate fetal haemoglobin in all patients with SCD and β-thalassemia through a drug that targets a key factor responsible for the natural silencing of fetal gene expression at birth. This Seeding Drug Discovery award aims to deliver a new targeted treatment for the haemoglobin disorders.

Development of small molecule inhibitors of the Pseudomonas aeruginosa biofilms to treat chronic infections in cystic fibrosis patients

Cystic fibrosis is the most common lethal, hereditary disease in Caucasian populations, affecting 1 in every 3,500 births in Europe with a current life expectancy of about 38 years.

Most disease-related morbidity and mortality in CF is caused by progressive lung disease as a result of bacterial infection and airway inflammation, primarily associated with the effects of chronic Pseudomonas aeruginosa (PA) lung infection and the persistence of PA biofilms.

The Trust has awarded Antabio €4.0m over 2 years to fund the development of a small molecule inhibitor of PA biofilms to be used in combination with standard-of-care antibiotics. The objective of the project team, led by Principal Investigator Dr Martin Everett, Head of Biology at Antabio, is to identify a potent and selective lead series with efficacy in animals which will be capable of further development into a drug to augment the effectiveness of antibiotic therapy and result in enhanced suppression of the infection.

Novel inhibitors of MAP4K4 (HGK), an acute therapy to prevent cardiac muscle cell death following myocardial infarction

Heart disease is the most frequent source of death and disability worldwide, most especially as heart attacks (cardiac muscle cell death from obstructed blood flow to the heart). Its severity is due in part to heart muscle's inability to rebuild itself as most other tissues can. One potential strategy, to enhance standard therapies like “clot-busting” drugs and stents, is to suppress cell death directly by protecting the injured, jeopardized muscle cells.

Professor Michael Schneider at Imperial College London has identified the enzyme MAP4K4 as a key regulator of cardiac cell death and has devised novel, potent, selective drug-like inhibitors to protect human cardiac muscle grown in the laboratory. This Seeding Drug Discovery Award will enable the innovative use of human cardiac muscle grown from stem cells to pinpoint the molecules responsible for cardiac injury and will take the programme of research the essential steps further, towards the development of MAP4K4 inhibitors as clinically workable compounds.

Optimisation of a series of hits against trypanosome phosphofructokinase to give a lead for treatment of the neglected disease Human African Trypanosomiasis

Human African Trypanosomiasis (sleeping sickness) is a neglected disease which is transmitted by tsetse flies. Without treatment death is inevitable and current drugs are poorly effective.

Professor Malcolm Walkinshaw of the University of Edinburgh and colleagues are working on developing a new drug for sleeping sickness based on understanding the biology of the T. brucei parasite that causes the disease. T. brucei gets its energy from the breakdown of glucose (glycolysis) obtained from host blood for survival. The proteins used for this process (so-called glycolytic enzymes) provide the parasite with its only source of energy (ATP molecules).

The compounds already identified in this project have been shown to kill the parasite by specifically inhibiting glycolysis. High throughput screening against one of the glycolytic enzymes (PFK) identified three chemically different families of inhibitors each capable of killing T. brucei parasites. The objective of this project is to design and synthesise related compounds to improve potency so that very low (nanomolar) concentrations of compound are needed to kill parasites.

Highly selective small molecule drug leads for use in blocking tumour epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC)

Many forms of breast cancer currently respond well to modern targeted treatments – where drugs are designed to inhibit individual protein "targets" in the cancer. But around one-in-five to one-in-ten breast cancers, termed "triple negative breast cancers", cannot be treated this way because no target responsible for this cancer has been identified.

These cancers have a higher rate of spread, are more likely to return following chemotherapy, and thus are more likely to become terminal. Researchers at the biotechnology company BerGenBio have identified a novel target that is present in many triple negative breast cancers. The objective of this project is to develop two drug-like lead series against this new target and to develop potential new drugs for the treatment of triple negative breast cancer.

Structure-aided discovery of CaMK1D kinase inhibitors as targeted therapeutic agents for breast cancer

Kinases are important targets for blocking cancer progression. However, many remain to be exploited. For example, no drugs are yet available to specifically inhibit any kinase which is switched on by a regulatory protein called calmodulin. Nonetheless, faulty expression of these “CaMK” enzymes is now thought to play a key role in breast cancer progression.

The Wellcome Trust has funded the CAMSEED consortium to discover small molecule inhibitors for a CaMK protein involved in basal-like breast cancer. The three dimensional structure of this target has been solved by the Structural Genomics Consortium and Professor Stefan Knapp at the University of Oxford. Interactions with small molecules are being screened by Professor Michael Overduin’s lab at the University of Birmingham using superconducting magnets and high throughput robots at the national HWB-NMR facility. The design of improved inhibitors that can enter cells and selectively block the oncogenic state is being led by Professor Peter Fischer at the University of Nottingham, with Colin Kenyon at CSIR, Pretoria, designing deuterated analogs for enhanced activity. The result of the two year project is expected to be a set of lead molecules for development as potential therapeutic agents for breast cancer, and may yield a new approach for using nature’s own inhibitory mechanisms to block cancer-causing kinases.

Design and development of AMPA receptor modulators with a much improved safety profile as novel drugs for treating the cognitive dysfunction associated with schizophrenia and other CNS disorders

Around 1% of the population will suffer from schizophrenia at some point in their life. Symptoms such as paranoia and/or hearing voices can be reasonably well treated by existing medications.

However, these drugs have little effect on the other symptoms (lack of motivation and impaired social function) and impaired cognition, including difficulties with attention, memory and problem-solving that result in a “brain fog”. These largely untreated symptoms remain a huge barrier to the resumption of a fully functional, “normal” life for these individuals and are associated with an annual estimated cost in the UK alone of around £12 billion.

Professor Simon Ward from the University of Sussex has received a Seeding Drug Discovery Award to identify and develop drug which is a selective modulator of the AMPA receptor which has the potential to provide an innovative new treatment for patients with schizophrenia. If successful the team expect to have a compound ready for clinical evaluation in just over three years time.

Nerve cells (neurons) communicate with each other by releasing chemicals known as neurotransmitters that interact with proteins called receptors on adjacent neurons. Levels of the neurotransmitter glutamate, which is crucial for normal cognitive function, are altered in schizophrenia. A specific subtype of glutamate receptor, the AMPA receptor, is thought to be associated with cognition and therefore increasing AMPA receptor function should improve cognitive performance in schizophrenia and thereby addressing an unmet need and revolutionizing the functional outcome of this patient population.

Discovery of new leads for the treatment of Human African Trypanosomiasis

Human African Trypanosomiasis (HAT) is a deadly disease caused by the T. brucei parasite that is prevalent throughout 36 sub-saharan African countries. The most serious form of the disease occurs when the parasite enters the Central Nervous System (CNS), causing significant neurological damages that are lethal if the infection is not treated. The current treatments cannot be administered orally and have serious safety liabilities which make them largely inadequate for mass administration and disease elimination programs.

The Novartis Institute for Tropical Diseases (NITD), an integrated part of the Novartis Institutes for BioMedical Research, is a drug discovery organization dedicated to the identification and early development of novel treatments for neglected tropical diseases. Through several chemical libraries screens, NITD and its collaborators have identified several thousands of new compounds (hits) potently active against the T. brucei parasite. The proposed research aims to triage and characterize these hits with the objective of identifying new compound classes compatible with their target product profile of an effective, safe, cheap and orally available new HAT treatment.

Apolipoprotein E4 as a therapeutic target for Alzheimer's disease: Identification of small molecule structure correctors to prevent apolipoprotein E4-associated neuropathology

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). Indeed, one in four people carry the apoE4 gene, whereas 65 to 80% of all AD patients have at least one copy of apoE4.

The apoE protein, which functions in the normal maintenance and repair of nerve cells, occurs in two major forms: apoE3 and apoE4. ApoE3 is often referred to as the normal form, while apoE4 differs from apoE3 by the change of a single amino acid residue (1 out of 299). This single change causes apoE4 to have an abnormal structure and function. As a result of this abnormal structure, the production of apoE4 in nerve cells sets off a chain of events that, over time, leads to neuronal degeneration and cell death. Believed to be an intruder, apoE4 is attacked by a protease enzyme and cut into smaller toxic fragments. These fragments then wreak havoc on many vital structures in the cells.

Robert W Mahley, MD, PhD, and his colleague Yadong Huang, MD, PhD, have identified small molecules that correct the abnormal structure of apoE4, mitigating its harmful effects by converting it to the functionally normal apoE3. The Trust has awarded $2.5 million over two years to Dr Mahley and the Gladstone Institutes to develop new chemical entities that target apoE4 in the brain in order to prevent the development of AD. Under the award, Gladstone will collaborate with San Francisco-based chemoinformatics company Numerate for chemistry expertise.

Fragment-based lead discovery against the protein-protein interaction between Aurora A and TPX2 for the treatment of cancer

The Wellcome Trust has awarded over £2.3 million to Chris Abell, John Skidmore and co-workers at the University of Cambridge to use fragment-based approaches for the generation of molecules which disrupt the interaction between the kinase Aurora A and the regulatory protein TPX2.

Such compounds are expected to have utility in the treatment of a number of solid and haematological cancers, with one particular focus being reversal of taxane resistance in solid tumours. The project will generate lead compounds suitable for screening in cancer cell-lines and animal models to further validate the target and will also provide leads for future optimisation towards a drug. This funding follows on directly from an ongoing Strategic Award pioneering the use of fragment-based approaches against protein-protein interactions, which used biophysical screening and X-ray crystallography to generate the fragment leads for the planned project.

A stream-lined lead optimization project with the potential to deliver first in class small molecule inhibitors of Respiratory Syncitial Virus (RSV)

RSV is one of the most important respiratory pathogen with 64 million infections and 160,000 deaths estimated worldwide annually. RSV infection is responsible for more infant hospitalizations than other viral infections such as influenza.

Susceptible populations are premature infants, children, transplant patients, the elderly and people of all ages with heart failure and lung disease. In addition, severe infection in infancy is linked to the later development of asthma. In the elderly in the US it was shown that RSV infection caused 177,500 hospital admissions and 14,000 deaths over a period of 4 years. Hospitalization costs alone were estimated at more than $1 billion.

re:VIRAL Ltd is focused on development of novel antiviral treatments for RSV. The Company has been granted an Seeding Drug Discovery award from the Wellcome Trust to develop novel small molecule RSV fusion inhibitors up to completion of preclinical studies. This project is a collaboration between re:VIRAL Ltd. and the University of Sussex Drug Discovery group. The key goals of this project are to identify a drug candidate suitable for progression into studies in man and novel back compounds with the ambition of developing the first approved therapy for RSV.

Next generation broad-spectrum antifungal treatment – development of a fungal proton pump inhibitor drug candidate

Fungal infection is a serious problem, especially for critically ill patients. There is an increase in the number of infections that cannot be treated with the medicines available today. This is in part caused by the increased number of infections with fungi that are resistant to existing drugs but also due to the appearance of treatment resistant rare types of fungus and the increased use of immunosuppressants to treat cancer and transplant patients.

The Wellcome Trust has funded Pcovery to develop a new drug with a novel mechanism of action for the treatment of serious fungal infections. The project will target a specific protein that is distinct for fungal cells, essential for fungal survival, and highly conserved across a number of fungal species. The hope is to identify a drug like compound, which will inhibit the function of the target protein and kill off the fungi without affecting the patient. Due to this novel mechanism of action it is expected that the drug will be active against fungi that are resistant to other antifungal drugs. It is also anticipated that the drug will have few side effects.

Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach

Prof Rabbitts and colleagues from the Weatherall Institute of Molecular Biology have been awarded Seeding Drug Discovery funding to develop small molecules specifically targeting the RAS-effector protein-protein interactions.

The RAS family of oncogenes is among the most frequently mutated in human cancers. Using minimal antibody fragments, the group has characterized an anti-RAS VH segment whose binding site covers the region of RAS where the signal transduction effector proteins bind, the “switch region.” In models of lung cancer this anti-RAS VH inhibits tumourigenesis, thus validating the mutant RAS-effector interaction as a therapeutic target. Using two different approaches small molecules have been identified that bind to RAS at the same point of contact as the anti-RAS VH. The Seeding Drug Discovery Award will be used to develop these hits through to leads and ultimately the identification of a preclinical development candidate.

Design and optimisation of new chemical entities that prevent the neurotoxic oligomerization and misfolding of both β-amyloid and tau proteins: A disease modifying therapeutics approach for Alzheimer’s Dementia

Wellcome Trust has awarded a grant to TREVENTIS Corporation to discover a disease-modifying drug for the treatment of Alzheimer's disease (AD). Numerous studies support the causative role of β-amyloid (Aβ) and tau in the aetiopathogenesis of AD.

These proteins tend to abnormally "clump" (protein misfolding) and give rise to neurotoxic aggregates of β-amyloid (plaques) and tau ("tangles"), the pathological hallmarks of AD. In vitro studies have identified that Aβ can be neurotoxic when in small aggregates. Since disease-modifying drugs represent the most desirable therapeutic approach to AD, protein misfolding of Aβ and tau represents a potential target in the rational design of a drug.

The ultimate goal of this research is to discover a disease-modifying new chemical entity for the treatment of AD that is efficacious and safe. This goal will be achieved by optimizing a class of small organic molecules capable of binding to both β-amyloid and tau, blocking their misfolding. A new series has recently been identified that are drug-like, potent anti-aggregants and penetrate the Central Nervous System. Funding under this award will enable the discovery of a lead candidate with completed pre-clinical pharmacokinetic and toxicology package.

Inhibition of small-conductance Ca2+-activated potassium (SK) channel as a novel concept for the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia (irregular heart beat), affecting an estimated 4.5 million people in the EU. AF mainly affects the elderly population and lifetime risk for developing AF is 25% for individuals over 40 years of age.

AF is associated with impaired quality of life, increased rate of hospitalisation, and increased risk of stroke and death. The Wellcome Trust has funded the Danish Biotech company Acesion Pharma to develop a novel pharmacological treatment for the acute cardioversion of AF to normal heart rhythm (sinus rhythm). The project aims to identify a compound that selectively blocks the so-called SK channel, a novel biological target for AF treatment.

Currently used medicines against AF are only moderately effective in cardioversion and have risk of serious adverse effects. There is therefore a significant medical need of new treatment options with better safety profile and higher efficacy. Based on Acesion Pharma’s existing know-how on SK channels and compounds blocking this ion channel, it is envisaged that such a compound could become a safer and more efficacious drug for AF.

GSK Diseases of the Developing World Discovery Engine

GSK's Tres Cantos Medicines Development Campus in Madrid, Spain has received a commitment from the Wellcome Trust to provide up to £5m in support of its open approach to discovering and developing urgently needed new treatments for diseases of the developing world.

The funding will move early-stage research to the next level, to find new medicines for diseases such as TB, malaria, Leishmaniasis and sleeping sickness. Scientists from around the world will work in collaboration with GSK drug discovery experts at its facility in Tres Cantos, Madrid which also houses GKS's Open Lab. The funding will provide the opportunity to progress the most promising projects underway by independent scientists at the Open Lab and from GSK's own research portfolio. The overarching goal of the investment is to develop two high-quality experimental drugs over the next five years.

A Centre of Excellence for lead optimisation for diseases of the developing world

There is an urgent need for new drugs to treat the major infectious diseases of the developing world, such as TB, malaria and African sleeping sickness. However, despite significant efforts in early stage drug discovery, there is a bottleneck when it comes to the lead optimisation stage of molecules targeting these diseases.

To address this need Professor Paul Wyatt and colleagues at the Drug Discovery Unit (DDU) at the University of Dundee, with joint funding from the Wellcome Trust and Bill & Melinda Gates Foundation, are establishing “A Centre of Excellence for Lead Optimisation for Diseases of the Developing World.”

The initial focus will be on TB, where the strategy is to identify a portfolio of TB Lead Optimisation projects through the DDU’s involvement with the HIT-TB consortium and TB Drug Accelerator Program which are working to generate leads through their screening programmes. The DDU as part of HIT-TB is already identifying and optimising multiple hit series that could be taken up by the team.

Novel small molecule inhibitors of metallo ß-lactamases for the treatment of multi-drug resistant Gram-negative infections

Multi-drug resistant Gram-negative bacteria account for most hospital infection worldwide (e.g. causing 25,000 deaths in Europe and extra healthcare costs/productivity losses of >€ 1.5 billion/year).

One of the most effective treatments is the use of carbapenem antibiotics. However, their usefulness is becoming increasingly compromised due to the rise of clinical resistance associated with the spread of genes encoding various metallo ß-lactamase (MBL) enzymes, primarily the carbapenemases NDM-1, VIM-1/VIM-2 and IMP-1.

The Trust has awarded Dr. Marc Lemonnier, CEO of Antabio, €4.7m over 3 years to fund the development of a novel, safe and efficacious pan-inhibitor of bacterial metallo ß-lactamases. The project team being led by Principal Investigator Dr. Marc Lemonnier, will develop drugs inhibiting these MBL enzymes, thereby returning carbapenems to full clinical effectiveness. The project will develop current leads to preclinical candidate nomination. It is envisaged that hospitalised patients suffering from complicated Gram-negative infections will be treated with a combination of Antabio’s new inhibitor coadministered with a carbapenem.

This therapeutic concept has been successfully proven by existing beta-lactam/ serine beta-lactamase inhibitor combinations such as Augmentin (Amoxycillin/Clavulanic acid). Since these combinations will not work against bacteria that are MBL producers, the medical need for MBL inhibitors remains critical. A beneficial feature of this paradigm is that oral activity is not required – carbapenems are taken intravenously, so a newly developed inhibitor can be coadministered through that route. This regimen simplifies the research and greatly increases the possibilities for success. A successful drug will alleviate patient suffering and reduce antibiotic failure in the clinic.

Discovery and development of novel small molecule inhibitors of the human Hyperpolarization activated Cyclic Nucleotide-gated 2 (HCN2) ion channel for the treatment of inflammatory and neuropathic pain

Treatments for inflammatory pain (IP) and neuropathic pain (NP) are frequently ineffective and have many side effects. Scientists in Professor Peter McNaughton's laboratory at the University of Cambridge have discovered that both IP and NP are abolished in mice when an ion channel is genetically deleted. This suggests that drugs blocking this ion channel will have value as novel analgesics.

IP is associated with injury, infection or chronic conditions such as arthritis; and NP is caused by nerve damage in conditions such as post-herpetic neuralgia and diabetic neuropathy. Both IP and NP can impose major limitations on lifestyle and working patterns and currently available treatments have major drawbacks. For example, non-steroidal anti-inflammatories cause gastric and renal damage; and opioids cause constipation and problems with tolerance and addiction.

The team aims to develop selective ion channel blockers, which avoid those that play essential roles in the heart and brain, and test them in animal models of IP and NP. In separate parallel studies they will use a known non-selective blocker to carry out proof-of-principle studies in human NP.

Small molecule inhibitors of the anti-apoptotic FLIP-FADD protein-protein interaction for the treatment of non-small cell lung cancer

In most organs and tissues, old cells are constantly dying and being replaced by new cells. This balance is critical for normal organ/tissue function and is maintained by a balance between new cells being created by cell division and old cells dying by a process known as "apoptosis".

One of the key characteristics of cancers is that the old cells do not die efficiently by apoptosis and therefore accumulate giving rise to a tumour that ultimately disrupts organ function. This block in apoptosis is also a major problem when it comes to treating cancers as the effectiveness of chemotherapies and radiotherapies usually rely on their ability to activate this type of cell death.

Dr David Longley’s team at Queen's University of Belfast have identified an intra-cellular protein called "FLIP" that plays a critical role in preventing the death of cancer cells treated with chemotherapy and radiotherapy. This protein plays a prominent role in increasing the resistance to therapy in a number of types of cancer, including non-small cell lung cancer, which is a particularly drug-resistant cancer and is the focus of this proposal. The project team plan to generate drugs to block FLIP's function and thereby overcome drug resistance and improve the therapeutic management of patients with this disease.

Perforin Inhibitors for the prevention of allogenic bone marrow stem cell transplant rejection

Perforin is a novel and tractable target, the inhibition of which would address significant unmet need in clinical allotransplantation and potentially, a number of other human disorders. An immunosuppressant targeting perforin would provide the first-ever therapy focussed specifically on one of the principal cell death pathways leading to transplant rejection.

The Trust has awarded AU$6.8m over three years to Professor Joe Trapani (Peter MacCallum Cancer Centre), Professor Bill Denny (University of Auckland), Professor James Whisstock (Monash University) and Professor Geoff Hill (Queensland Institute for Medical Research) for the development of small molecule inhibitors of perforin that could lead to more prevention of allogeneic bone marrow stem cell transplant rejection and therefore increase survival rates for many forms of cancer.

The team led by Professor Joe Trapani, have recently developed three classes of compounds which have been shown to block the action of perforin. Under the Trust funding the team will continue to characterise and improve on these compounds. These inhibitors will be assessed in specific models and then progressed into clinical candidates that could be ultimately assessed in drug trials for indications with significant unmet clinical need.

11b-HSD1 inhibition for disease modification and symptom control in Alzheimer's disease

Professor Brian Walker, Professor Jonathan Seckl and Dr Scott Webster, University of Edinburgh have identified 11b-HSD1 as a crucial amplifier of glucocorticoid action in liver, adipose tissue and CNS, have shown its pathophysiological significance in obesity, and have provided preclinical and clinical 'proof of concept' that 11b-HSD1 inhibition improves both Metabolic Syndrome and cognitive function in ageing.

Although their work has fuelled intense commercial interest in developing 11b-HSD1 inhibitors for metabolic indications, including type 2 diabetes, the opportunity to improve cognitive function has not yet attracted pharmaceutical companies. Under the latest round of funding, they will select the optimal clinical candidate and aim to progress these to Phase I clinical trials aiming at a memory improvement.

Development of a type B lantibiotic for treatment of Clostridium difficile infection

C. difficile infection (CDI) has increased in incidence and severity through the last decade to become the major cause of mortality amongst nosocomial infections. Currently, there are very few therapeutic options for CDI and recurrence of disease after initial successful therapy is a major health problem and burden to healthcare systems.

Novacta Biosystems Limited has embarked on development of a class of agents called type B lantibiotics which inhibit bacterial cell wall biosynthesis. The agents have promising properties for treatment of CDI in that given orally they are stable in the gastro-intestinal tract and not absorbed, their mechanism of action provides a good resistance prognosis and they have low toxicity.

Starting with the discovery of a new lantibiotic, deoxyactagardine B, a combination of biosynthetic modification at the genetic level and semi-synthetic chemistry yielded NVB302, a drug candidate with excellent activity against C. difficile and very little activity against the predominantly Gram-negative gut flora. This selectivity is believed to be important to allow the colonic flora to restore a barrier to re-infection. NVB302 is currently undergoing a phase I clinical trial in healthy volunteers.

Identification of retinoic acid receptor b agonists for the treatment of spinal cord injury

There are as yet no effective treatments for spinal cord injuries (SCI). The Trust has awarded £3.6 million to Dr Jonathan Corcoran, Dr Barret Kalindjian and Professor Thomas Carlstedt for the development of orally available small molecules for the treatment of SCI.

Researchers led by Dr Jonathan Corcoran have identified a novel signalling mechanism - the retinoic acid receptor b (RARb) signalling pathway - that can be stimulated in models of SCI leading to axonal outgrowth and functional recovery. The pathway is activated by small molecules known as retinoids and leads to the modulation of various proteins that are known to be involved in axonal outgrowth.

The award will allow the identification of novel RARb agonists which can be given orally to patients with SCI. Their use will be demonstrated in rodent models of SCI, and the work will ultimately lead to a clinical trial in human avulsion injury, which is one of many types of SCI.

Discovery of new drugs for the prophylaxis and treatment of dengue virus infections in humans

The dengue virus is endemic in most tropical and sub-tropical regions around the world, predominantly in urban and semi-urban areas. According to the World Health Organization 2.5 billion people, of which 1 billion children, are at risk of dengue infection.

An estimated 50 to 100 million cases of dengue fever, half a million cases of severe dengue disease and more than 20,000 deaths occur worldwide each year. Dengue is a leading cause of hospitalization and death amongst children in regions where dengue is present. There is no vaccine, nor a specific treatment or prophylaxis for dengue.

With Welcome Trust funding, Professor Johan Neyts (Rega Institute) together with the Centre for Drug Design and Discovery (CD3) at the University of Leuven (KULeuven) identified a novel class of potent inhibitors of dengue replication. The lead compounds in this series elicit activity against all four dengue serotypes with a large therapeutic window. This class of small molecule inhibitors has a good ADME-Tox profile and targets the virus via a unique mechanism. Furthermore the barrier to resistance is high and once obtained, the fitness of such variants is low. The project is now in a lead optimisation phase.

Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer

The enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix.

LOX also plays a role in stimulating the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. In model systems its inhibition significantly decreases cancer metastasis and increases survival. Since metastasis is responsible for over 90 per cent of cancer deaths these data validate LOX as an important therapeutic target in cancer.

Professor Caroline Springer and Professor Richard Marais from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX. They are applying a medicinal chemistry drug discovery approach underpinned by a strong programme in LOX biology with the aim of producing orally available, small molecular weight drugs that inhibit LOX activity for cancer treatment.

Novel small molecule inhibitors of the human cardiac acetylcholine activated current (IKACh) for the treatment of atrial fibrillation

Atrial fibrillation (AF) is an abnormal, disorganised, cardiac rhythm that originates in the upper chambers (atria) of the heart. It is the most common sustained cardiac arrhythmia encountered in clinical practice, with around 12 million sufferers worldwide and is gaining in clinical importance as the population ages.

AF is clinically significant because it contributes to the incidence of stroke and overall cardiovascular morbidity and mortality. Patients with AF have a five-fold increased risk for stroke; indeed, in the US approximately 15-25 per cent of all strokes can be attributed to AF. The treatment of AF is controversial and often problematic. Whereas electrical cardioversion restores sinus rhythm in many patients with AF, the maintenance of sinus rhythm often requires chronic treatment with anti-arrhythmic drugs.

Although there is a consensus amongst cardiologists that sinus rhythm control with anti-arrhythmic drugs is the preferred and most effective treatment of AF, none of the existing drugs are able to maintain rhythm without significant negative side effects. Consequently new anti-arrhythmic drugs are desperately needed. Xention Limited has received Seeding Drug Discovery funding to develop an orally active drug for the safe and effective treatment of AF with a substantially improved safety profile compared to current therapies.

Allergen Delivery Inhibitors: Preclinical evaluation Allergen Delivery

Inhibitors offer the potential to combine alleviation of asthma with allergy prophylaxis using small molecule inhaled therapy. Researchers at St George’s, University of London and the University of Manchester have employed structure-based drug design to develop inhibitors that selectively target house dust mite cysteine peptidases, enzymes that make significant contributions to the development, maintenance and escalation of allergic diseases including asthma. The programme’s candidate drug (CD 1) displays in vivo efficacy in animal models with a good duration of action when delivered to the airways. CD 1 is supported by several developable back-up compounds from chemically distinct and mechanistically distinct series. A patent portfolio is being created and Innovations is seeking a development and commercialisation partner for this programme.

Discovery and development of novel glioblastoma treatment that selectively reduces Bmi-1 expression in tumour stem cells

BMI1 is a well-established oncogene that has been shown to be over expressed in tumour cells and necessary for cancer stem cell survival. PTC was awarded funding through the Wellcome Trust Seeding Drug Discovery initiative to identify novel small molecules that target BMI1.

It is widely accepted that a subpopulation of tumor cells, possessing intrinsic chemo-resistance and expressing many characteristics of normal stem cells, is responsible for treatment failure and relapse across multiple tumor types. BMI1 is a transcriptional repressor necessary for efficient cell division necessary for the renewing of adult hematopoietic stem cells as well as adult peripheral and central nervous system stem cells. BMI1 is widely over-expressed in human cancers and is critical in the development of glioblastomas, leukemias, lymphomas, and lung cancers. The level of BMI1 protein is positively correlated with disease grade and poor prognosis. By inhibiting BMI1 protein function and levels, PTC is targeting the resistant cancer stem cell fraction within tumours.

PTC has identified compounds that potently reduce the levels of endogenous BMI1 protein in multiple cell lines at low nanomolar concentrations. Consistent with the function of BMI1, PTC's compounds preferentially kill tumor cells, and in particular tumor stem cells, sparing normal primary progenitor cells. PTC's compounds selectively decrease the level of BMI1 in vivo on oral dosing in pharmacodynamic xenograft models of several tumor types. At higher doses of compound, this inhibition resulted in a nearly total control of tumor growth in multiple xenograft models of fibrosarcoma, glioblastoma, and leukemia. The program is currently in late lead optimization with the goal of identifying an orally available Development Candidate for the treatment of chemotherapy- and radiation-resistant cancers.

Novel bacterial DNA synthesis inhibitors for the treatment of nosocomial infections caused by multi-drug resistant Gram-negative bacteria

PTC Therapeutics, Inc. (PTC) has been awarded funding from the Seeding Drug Discovery initiative for a programme targeting the treatment of infections caused by multidrug-resistant Gram-negative bacteria. PTC has identified a novel structural class of molecules that selectively inhibit bacterial DNA synthesis and have bactericidal activity.

These molecules are predominantly active against Gram-negative bacteria although several analogs in the series also have activity against Gram-positive species, including methicillin-resistant S. aureus (MRSA). The PTC compounds are potent against Gram-negative bacteria that are resistant to marketed antibiotics. Representative compounds have good pharmaceutical properties and are efficacious in murine models of systemic E. coli infection. The anti-infective program at PTC is currently in lead optimization and advancing towards identifying a development candidate as a potential first-in-class drug for the treatment of life-threatening infections caused by Gram-negative multidrug-resistant bacteria.

Development of a small molecule inhibitor of EBNA1 to treat Epstein-Barr Virus (EBV) Latent Infection and Associated Disease

Epstein-Barr Virus (EBV) is estimated to be responsible for ~1% of all human cancers worldwide including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, gastric carcinoma, NK/T cell lymphoma, and lymphoproliferative disease in the immunosuppressed.

The World Health Organisation classifies EBV as a type I carcinogen. Maintenance of latent EBV in infected cells depends on the continuous expression of one viral protein, EBNA1. The essential role of EBNA1 in cell proliferation, transformation and lymphomagenesis associated with EBV malignancies makes it an attractive target for drug discovery and development.

Recently, the crystal structure of EBNA1 has been determined and revealed a druggable surface within its DNA binding domain. Exploiting this property, the team of Professor Lieberman at the Wistar Institute in Philadelphia completed a successful high-throughput screening campaign.

Supported by a three year Seeding Drug Discovery award the team will now use medicinal chemistry and structure-based drug design methods to optimize promising starting points into small molecule inhibitors of EBNA1. The goal of this project is the development of a pre-clinical candidate ready to be taken into Phase 1 first in human clinical trials. This innovative project has the potential to deliver a completely novel anti-viral in a field of significant unmet medical need.

Development of a membrane-targeted antibiotic for complicated skin and skin structure infections caused by multidrug-resistant bacteria

The lack of treatments currently available for multi-drug resistant bacteria is one of the most pressing global health issues today. This crisis has been clearly noted by key UK, European and US opinion leaders and government organisations. Professor Matthew Cooper and his colleagues at the University of Queensland have received a Seeding Drug Discovery award to help to address this problem. The team are using a natural product which has been modified to bind more tightly to bacterial membranes, and not bind to human cell membranes. They plan to develop this modified natural product into a 'best in class' antibiotic for the treatment of infections by bacteria and resistant superbugs.

Identification of lead Leishmania proteasome inhibitors

Leishmaniasis is a widespread parasitic disease with frequent epidemics in the Indian subcontinent, Africa and Latin America. The disease is responsible for about 40,000 deaths each year, and substantial morbidity. In its most severe form, visceral leishmaniasis (or kala azar), the disease is characterised by parasitic invasion of internal organs and is almost always fatal if left untreated. Several drugs are available, but they suffer from multiple shortcomings such as toxicity, parasite resistance, and length and cost of treatment.

A research team led by Dr Frantisek Supek at the Genomics Institute of the Novartis Research Foundation, San Diego, has previously identified a novel drug target for treatment of visceral leishmaniasis, the parasite proteasome. Small molecules that selectively inhibit this parasite enzyme have shown promise in curing not only leishmaniasis but also other kinetoplastid infections, including Chagas disease and sleeping sickness.

The aims of this project are to discover selective inhibitors of Leishmania proteasome by high throughput screening, and to optimise identified scaffolds towards orally available small molecules with efficacy in the mouse model of visceral leishmaniasis. Such compounds would be suitable for toxicity studies in support of clinical testing.

Identification of PARP inhibitors for cancer therapy

While effective treatments for many forms of cancer exist, therapies that are tailored for patients with niche forms of the disease, such as triple negative breast cancer are currently unavailable.

The Trust has awarded £3.9 million over three years to Prof. Alan Ashworth, FRS, Dr. Christopher Lord, Prof. Caroline Springer and Prof. Laurence Pearl, FRS, for the development of orally available small molecules that could target specific cancer subtypes.

Researchers led by Prof Alan Ashworth and Dr Christopher Lord have pioneered the exploitation of novel therapeutic approaches such as synthetic lethality and the use of PARP inhibitors in cancer treatment. PARP (Poly ADP-Ribose Polymerase) enzymes modify proteins and control cell function by catalyzing the addition of poly (ADP-ribose) polymers onto substrates.

With funding from the Trust, Ashworth, Lord, Springer and Pearl, in collaboration with Domainex, will develop novel small molecule inhibitors that target additional PARP superfamily members. These inhibitors will be assessed in specific tumour models and then progressed into clinical candidates that could be ultimately assessed in drug trials that target cancer subtypes for which there is significant unmet clinical need.

The use of fragment-based drug discovery to identify novel drug candidates that modulate the BRCA2-RAD51 interaction for the treatment of cancer

The Trust has awarded over £2.4 million to Chris Abell, Tom Blundell, Marko Hyvonen, Grahame McKenzie and Ashok Venkitaraman at the University of Cambridge to use fragment-based approaches to design and make molecules that disrupt the interaction of two important proteins in human cells, the recombinase RAD51 and the product of the breast cancer-associated gene BRCA2.

These proteins are involved in the repair of DNA breakage, and blocking their interaction should result in sensitization of cancer cells to DNA damage, e.g. by radiation, or directly induce cancer cell death during proliferation. Potent compounds will be developed by synergistic use of X-ray crystallography and synthetic organic chemistry, and improved in a highly focused way to make sure they are safe and suitable for development into possible drug candidates. The lead compounds will be tested against different cancer cell lines to identify susceptible cancers, the most probable therapeutic target being lung cancer.

This funding follows on directly from a Translation Award to pioneer the use of fragment-based approaches against protein-protein interactions. That project established the use of biophysical methods, especially NMR spectroscopy and X-ray crystallography to identify fragments that bound at specific sites on a protein interface and to iteratively grow these fragments into successively more potent compounds.

A new approach to the treatment of invasive pneumococcal diseases

Streptococcus pneumoniae causes a very high number of cases of pneumonia, meningitis and bacteraemia, worldwide. Despite using antibiotics that kill the bacterium, a large number of patients still die and in meningitis, many survivors have profound neurological handicap. This is because the bacterium produces a very damaging virulence factor that is not inhibited by antibiotics.

This problem constitutes an unmet medical need that Professor Peter Andrew and colleagues from the University of Leicester are proposing to fulfill. They have identified that small molecules can inhibit this virulence factor and are effective in vivo. The team have been awarded funding through the Seeding Drug Discovery initiative to identify new small molecules and through a programme of medicinal chemistry, combined with in vitro and in vivo testing, to identify lead compounds with appropriate efficacy, pharmacokinetics and toxicology. The aim is that giving such molecules will reduce the number of patients that die or suffer handicap as a result.

Novel aminoglycosides for the treatment of multi-drug resistant Gram-negative bacteria

Aminoglycosides are a proven class of antibacterials that remain in extensive clinical use despite growing drug resistance. The Trust has provided a programme-related investment of $8 million (£4.1 m) to San Francisco based Achaogen Inc, to develop novel aminoglycoside compounds to tackle emerging resistance. Achaogen will progress a lead scaffold with activity against Staphylococcus aureus and highly resistant Enterobacteriaceae and a separate chemical series with extended spectrum that also includes multi-drug resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Both scaffolds will be advanced via in vitro and in vivo efficacy, pharmacokinetic, and safety assays, culminating in the identification of a clinical candidate.

Retinoic acid receptor a agonists for the treatment of Alzheimer's disease

The current licensed treatments for Alzheimer's disease improve the symptoms that people experience but do not alter the progression of the underlying disease changes in the brain. Most of the attempts to develop new treatments have focused on altering deposits of the amyloid protein in the brain, but despite more than a decade of intensive research this has still not yielded any new therapies in the clinic.

The studies of Dr Jonathan Corcoran of King's College London highlight a specific retinoic acid receptor (RAR)a agonist as a novel and exciting target for the development of new treatments. This agonist has two mechanisms of action - it regulates amyloid deposits in the brain and also plays a key role in the survival of neurons. In their project they will generate novel RARa agonists for the treatment of Alzheimer's disease.

Selective glucocorticoid receptor agonists for the treatment of inflammatory conditions

Research by Professor David Ray and his team at University of Manchester has identified how to modulate the function of the glucocorticoid receptor. The glucocorticoid receptor responds to both natural hormones and synthetic glucocorticoids to inhibit the inflammatory response. Inflammation lies behind many important human diseases, including rheumatoid arthritis, and opening up novel approaches for therapy offers new hope for these chronic, disabling conditions.

The award will allow development of new molecules capable of harnessing the glucocorticoid receptor for treatment of multiple inflammatory diseases, without the wide range of side effects that currently limit use of conventional drugs. If successful the research will lead to an orally active drug for use in inflammatory arthritis within five years.